Evolution of Cryptococcus neoformans Strains from Patients with HIV/AIDS

HIV/AIDS 患者的新型隐球菌菌株的进化

• 批准号: 10199975
• 负责人: John R. Perfect
• 金额: $ 37.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199975
• 关键词: AIDS population; AIDS/HIV problem; Age; Animal Model; Animals; Antifungal Agents; Basic Science; Behavior; Bioinformatics; Biological Assay; Brain Diseases; Cell Size; Cell Wall; Cell membrane; Cells; Censuses; Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Clinical; Communities; Complex; Country; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Data; Disease; Disease Outcome; Drug Targeting; Drug resistance; Encapsulated; Environment; Evolution; Explosion; Future; G Cells; Genes; Genetic; Genetic Crosses; Genetic Transcription; Genome; Genomics; Genotype; Goals; Growth; Health Care Costs; Healthcare Systems; High temperature of physical object; Human; Immune response; Immunocompromised Host; In Vitro; Infection; Infrastructure; Internet; Investigation; Knowledge; Libraries; Link; Lung diseases; Melanins; Meningitis; Metabolic; Molecular; Morbidity - disease rate; Movement; Mus; Oryctolagus cuniculus; Outcome; Partner in relationship; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytosis; Phenotype; Phylogenetic Analysis; Plague; Population; Populations at Risk; Production; Prognosis; Recording of previous events; Research; Resources; Risk; Spottings; Structure of thyroid parafollicular cell; System; Treatment Protocols; Validation; Virulence; Virulent; Work; Yeasts; aggressive therapy; antiretroviral therapy; base; cell capsule; cost; design; fitness; fungus; genetic linkage; genetic pedigree; genome sciences; genome sequencing; genome wide association study; genomic data; genomic locus; health care availability; human data; human disease; human pathogen; insight; mortality; pathogen; pathogenic fungus; phenotypic data; population genetic structure; public health relevance; response; robotic system; screening; stressor; sugar; tool; treatment strategy; whole genome

Abstract This competitive renewal will continue to work on understanding the population genetic structures of Cryptococcus neoformans. With this massive genome sequencing data, we will expand it and add a functional and/or translational focus. Importantly, the sequence data are integrated with phenotypic data, animal models and human infection outcomes to help understand the genetic components that make it a deadly human pathogen.Cryptococcus neoformans represents a group of encapsulated basidiomycetous yeasts that continue to produce hundreds of thousands of cases of meningitis each year with mortality rates of 15 to over 50% depending on the health care systems and no new antifungal agents have been discovered for its treatment in 25 years. In this proposal, we will use whole genome sequences to direct a research platform to complete two Specific Aims that are framed in questions. Specific Aim 1 is: What are the genotypic and phenotypic differences between clinical and environmental strains. Specific Aim 2 examines the following question: Within clinical isolates that have already produced disease, why are some strains more virulent or aggressive than others? The goal of this proposal is three- fold. First, to use whole genome sequencing (WGS) and GWAS in a large number of strains linked to functional data in order to dial down into wild-type strains and find specific genes and/or networks important to C. neoformans fitness/survival in the mammalian host. Thus, we will identify potential weak spots in the fungus to be used for antifungal drug targets. Second, to genetically identify “bad actor” strains producing more aggressive disease behaviors that could be identified for the treating clinician to appreciate and thus adjust treatment regimens based on this knowledge of the strain’s pathobiology. Finally, this study will create a substantial infrastructure addition of a library of well-characterized wild-type strains for use by the entire cryptococcal community for future pathobiology work.

摘要 这一竞争性更新将继续致力于了解大熊猫的种群遗传结构。 新生隐球菌。有了这些海量的基因组测序数据，我们将对其进行扩展，并添加功能 和/或翻译焦点。重要的是，序列数据与表型数据、动物模型 和人类感染结果，以帮助了解使其成为致命人类的遗传成分 病原菌。新生隐球菌代表一组被包裹的担子菌酵母菌 每年造成数十万例脑膜炎，死亡率从15%到50%以上 取决于卫生保健系统，而且在#年还没有发现新的抗真菌药物来治疗它。 25年。在这个方案中，我们将使用全基因组序列来指导一个研究平台来完成两个 在问题中框定的具体目标。具体目标1是：什么是遗传型和表型 临床菌株和环境菌株之间的差异。《特定目标2》考察了以下几点 问：在已经产生疾病的临床菌株中，为什么有些菌株更多？ 比其他人恶毒还是咄咄逼人？这项提议的目标有三个方面。第一，使用全基因组 对大量菌株进行测序(WGS)并将其与功能数据相关联，以便向下拨入 野生型菌株，并找到对新生梭菌适应/生存至关重要的特定基因和/或网络。 哺乳动物宿主。因此，我们将确定真菌中潜在的弱点，以用于抗真菌药物 目标。第二，从基因上鉴定产生更具攻击性疾病行为的“坏演员”菌株 可以被识别以供治疗临床医生欣赏，从而基于此来调整治疗方案 了解该菌株的致病生物学知识。最后，这项研究将创建一个实质性的基础设施 供未来整个隐球菌界使用的特征良好的野生型毒株文库 病理生物学的工作。